Acquired Cross-Resistance through MYC Amplification in Small Cell Lung Cancer - PROJECT SUMMARY Small cell lung cancer (SCLC) afflicts more than 30,000 patients per year and is rapidly fatal in 94% of cases, with median survival of less than one year. Although untreated SCLC is highly responsive to first-line chemotherapy, benefit is temporary and following relapse, resistance often extends to a broad spectrum of DNA damaging agents. Furthermore, investigational therapies in clinical trials are often confounded by the same cross-resistance that hinders standard second-line agents. Although critically important, cross-resistance is difficult to study experimentally, as it requires a model system that faithfully reproduces clinical outcomes and is adequately powered to capture inter-tumoral molecular heterogeneity. We have generated a panel of 72 patient-derived xenograft models (PDXs) of SCLC from biopsy specimens and circulating tumor cells (CTCs). For both standard chemotherapy and investigational agents, these models faithfully mirror patient responses. However, unlike the patient experience, multiple strategies can be compared for identical tumors. We generated a thorough and quantitative chemosensitivity profile of each PDX model. This profile confirmed that models that are resistant to one regimen are usually resistant to all, demonstrating cross-resistance. Nearly all these cross-resistant models were from previously treated patients. For five SCLC patients we derived PDX models before treatment and again after relapse. The post-relapse models were consistently more resistant, reflecting the changes in the patient’s cancer. These paired models are powerful research tools because they can show directly what made the cancer resistant. In one of these pairs, the relapsed model had a high-level MYC amplification on a circle of extrachromosomal DNA (ecDNA). We demonstrated that the extrachromosomal MYC amplification (ecMYC) was the cause of cross-resistance in that model. We expanded this study to the whole PDX panel and found significant enrichment of ecDNAs with MYC, MYCN or MYCL in cross-resistant models from relapsed patients. These ecMYC/L/N amplifications are the first alterations in the genomes of SCLC tumors to be demonstrated to drive cross-resistance. This important discovery leads to major questions. First, how do ecMYC, ecMYCL or ecMYCN cause resistance? MYC has many cellular functions, and this is likely to be a challenging question, but one major insight is that the cells that have the highs numbers of ecDNAs and are most resistant appear to stop dividing. The second question is what are the other drivers of cross-resistance, in the PDX models that are negative for ecMYC/L/N? In at least one case, an ecDNA with a different gene, XRCC1, seems to cause resistance. Finally, how do we test for this in patients? We propose a way to test for these ecDNAs in the same CTCs that we used to build the PDX models. The goal of this work is to develop a plan of care for patients with relapsed SCLC that is tailored to the driver of resistance in their cancer.
